The similarities between the γ-secretase-mediated processing of AβPP and the Notch receptor suggest that the AβPP intracellular domain (AICD), like its Notch counterpart, could play a role in signal transduction. This idea is supported by yeast two-hybrid experiments, which show that the AICD can promote transcription of a reporter gene when bound to Fe65, a protein that interacts strongly with histone acetyltransferases (see related ARF news item). However, there is currently no evidence that AICD enters the nucleus, nor have any potential downstream targets of the intracellular domain been identified.
Steps toward addressing the latter shortcoming have been taken by an international collaboration lead by Frank LaFerla, University of California at Irvine, and including Michael Wolfe at Harvard Medical School and Bart DeStrooper at Flanders Interuniversity, Leuven, Belgium. The researchers report in tomorrow's Proceedings of the National Academy of Sciences that AICD plays an important role in intracellular calcium signaling.
The authors showed that mouse embryonic fibroblasts devoid of presenilin 1, the likely active component of γ-secretase, poorly mobilized intracellular calcium in response to external stimuli. Calcium signaling was also blocked by γ-secretase inhibitors, which blocked signal transduction as potently as they inhibited the protease. Furthermore, in AβPP-negative cells, Ca2+-signaling was markedly disrupted but could be rescued by transfection with whole AβPP or with just the AICD; transfection with an AβPP construct devoid of the AICD failed to restore signaling.
A role for AICD in regulation of endoplasmic reticulum (ER) calcium was suggested by the fact that PS1/PS2- or AβPP-negative fibroblasts, or those treated with γ-secretase inhibitors had lower ER calcium, an observation that agrees with previous data (Yoo et al 2000).
How the AICD may regulate signal transduction is uncertain but the authors found a 3-hour lag between inhibition of γ-secretase and inhibition of Ca2+-signaling, which would be sufficient time to modulate transcription.—Tom Fagan
- Leissring MA, Murphy MP, Mead TR, Akbari Y, Sugarman MC, Jannatipour M, Anliker B, Müller U, Saftig P, De Strooper B, Wolfe MS, Golde TE, Laferla FM. A physiologic signaling role for the gamma -secretase-derived intracellular fragment of APP. Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4697-702. PubMed.